PROJECT SUMMARY Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. IBD afflicts nearly 1.5 million people in the United States. The exact causes of IBD are unknown, but they are thought to generally involve dysregulated host immune responses to commensal microorganisms in genetically susceptible individuals. Tumor necrosis factor (TNF), a major immune cytokine, has a central role in the disease process. While anti-TNF therapies are a part of the medical regimen for many IBD patients, there is mounting evidence that the complete blockade of TNF signaling is not appropriate in the long-term for many. For example, most patients treated with anti-TNF biologics stop responding to the therapy within 5 years. We and others have demonstrated that TNF signaling through its lesser-characterized receptor TNFR2 has many beneficial functions on the repair of the colonic epithelial barrier, a crucial mitigating aspect of IBD, and on the regulation of immune cells including cytotoxic (CD8+) T lymphocytes and regulatory T cells. This application will follow-up on these novel observations to explore the mechanisms that underlie TNFR2's protective effects on CD8+ T cells and colonic epithelial stem cell populations in the setting of colonic injury and inflammation. Specifically, we will: 1) determine the mechanisms by which TNFR2 regulates the pathogenicity of CD8+ T cells in colitis, 2) elucidate the role of TNFR2 in regulation of CD8+ T cell subpopulations and their colonic localization, and 3) define the role of epithelial TNFR2 on colonic epithelial stem cell dynamics and mucosal healing. These studies will reveal important cellular and molecular patterns that may underlie the pathophysiology of IBD.